Frequency and Prognostic Impact of ALK Amplifications and Mutations in the European Neuroblastoma Study Group (SIOPEN) High-Risk Neuroblastoma Trial (HR-NBL1).

Détails

Ressource 1Télécharger: jco.21.00086.pdf (1430.48 [Ko])
Etat: Public
Version: Final published version
Licence: CC BY 4.0
ID Serval
serval:BIB_69028FD04004
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Frequency and Prognostic Impact of ALK Amplifications and Mutations in the European Neuroblastoma Study Group (SIOPEN) High-Risk Neuroblastoma Trial (HR-NBL1).
Périodique
Journal of clinical oncology
Auteur⸱e⸱s
Bellini A., Pötschger U., Bernard V., Lapouble E., Baulande S., Ambros P.F., Auger N., Beiske K., Bernkopf M., Betts D.R., Bhalshankar J., Bown N., de Preter K., Clément N., Combaret V., Font de Mora J., George S.L., Jiménez I., Jeison M., Marques B., Martinsson T., Mazzocco K., Morini M., Mühlethaler-Mottet A., Noguera R., Pierron G., Rossing M., Taschner-Mandl S., Van Roy N., Vicha A., Chesler L., Balwierz W., Castel V., Elliott M., Kogner P., Laureys G., Luksch R., Malis J., Popovic-Beck M., Ash S., Delattre O., Valteau-Couanet D., Tweddle D.A., Ladenstein R., Schleiermacher G.
ISSN
1527-7755 (Electronic)
ISSN-L
0732-183X
Statut éditorial
Publié
Date de publication
20/10/2021
Peer-reviewed
Oui
Volume
39
Numéro
30
Pages
3377-3390
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Résumé
In neuroblastoma (NB), the ALK receptor tyrosine kinase can be constitutively activated through activating point mutations or genomic amplification. We studied ALK genetic alterations in high-risk (HR) patients on the HR-NBL1/SIOPEN trial to determine their frequency, correlation with clinical parameters, and prognostic impact.
Diagnostic tumor samples were available from 1,092 HR-NBL1/SIOPEN patients to determine ALK amplification status (n = 330), ALK mutational profile (n = 191), or both (n = 571).
Genomic ALK amplification (ALKa) was detected in 4.5% of cases (41 out of 901), all except one with MYCN amplification (MNA). ALKa was associated with a significantly poorer overall survival (OS) (5-year OS: ALKa [n = 41] 28% [95% CI, 15 to 42]; no-ALKa [n = 860] 51% [95% CI, 47 to 54], [P < .001]), particularly in cases with metastatic disease. ALK mutations (ALKm) were detected at a clonal level (> 20% mutated allele fraction) in 10% of cases (76 out of 762) and at a subclonal level (mutated allele fraction 0.1%-20%) in 3.9% of patients (30 out of 762), with a strong correlation between the presence of ALKm and MNA (P < .001). Among 571 cases with known ALKa and ALKm status, a statistically significant difference in OS was observed between cases with ALKa or clonal ALKm versus subclonal ALKm or no ALK alterations (5-year OS: ALKa [n = 19], 26% [95% CI, 10 to 47], clonal ALKm [n = 65] 33% [95% CI, 21 to 44], subclonal ALKm (n = 22) 48% [95% CI, 26 to 67], and no alteration [n = 465], 51% [95% CI, 46 to 55], respectively; P = .001). Importantly, in a multivariate model, involvement of more than one metastatic compartment (hazard ratio [HR], 2.87; P < .001), ALKa (HR, 2.38; P = .004), and clonal ALKm (HR, 1.77; P = .001) were independent predictors of poor outcome.
Genetic alterations of ALK (clonal mutations and amplifications) in HR-NB are independent predictors of poorer survival. These data provide a rationale for integration of ALK inhibitors in upfront treatment of HR-NB with ALK alterations.
Mots-clé
Anaplastic Lymphoma Kinase/genetics, Child, Preschool, Clinical Trials, Phase III as Topic, Europe, Female, Follow-Up Studies, Gene Amplification, Humans, Infant, Male, Mutation Rate, N-Myc Proto-Oncogene Protein/genetics, Neuroblastoma/genetics, Prognosis, Randomized Controlled Trials as Topic, Risk Factors, Survival Rate
Pubmed
Web of science
Open Access
Oui
Création de la notice
14/06/2021 17:06
Dernière modification de la notice
14/05/2022 6:34
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